The overall goal of this proposal is to determine that peripheral somatostatin (SST) receptor activation is critical in controlling nociceptor excitability, reducing peripheral sensitization and promoting analgesia. SST, a peptide found in primary afferents, or its long lasting agonist Octreotide, has been shown to prevent peripheral sensitization. Peripheral sensitization of nociceptors is a key element that not only underlies primary hyperalgesia in the peripheral but also contributes to central sensitization. The proposal explores the use of an SST agonist in the periphery to reduce peripheral sensitization in inflammatory pain. The hypothesis is that peripheral SST receptors play a critical role in modulating nociceptor sensitization in normal and inflamed skin. The aims are to show that 1) SST receptors are on peripheral afferents and increase during inflammation; 2) peripheral SST receptor activation reduces the nociceptive responses and sensitization of nociceptors during inflammation; 3) peripheral SST receptor activation inhibits nociceptive behavioral responses in normal and inflamed animals; 4) SST receptors exert a tonic inhibitory influence over peripheral nociceptors; 5) SST agonists acts through non-opioid mechanisms; 6) that peripheral administration of SST agonists does not produce neurotoxicity; 7) endogenous SST can be released to help the body cope with inflammatory pain. Preliminary data suggest that SST2a receptors are localized on nociceptors in the glabrous skin in the rat. Activation of these receptors with Octreotide attenuates bradykinin-induced sensitization of nociceptors using an in vitro skin-nerve preparation and intraplantar injection of Octreotide attenuates formalin- and complete Freund's adjuvant-inducted nociceptor behaviors. The preliminary data suggests that SST exerts a tonic inhibitory control over peripheral nociceptors and that endogenous SST is released to help the body cope with inflammatory pain. Peripheral SST receptors offer novel targets for nociceptor modulation and are likely targets for further development of non-opioid therapies to aid in reducing the pain and long-term deleterious changes that can accompany inflammation.